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Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton

Abstract

The proto-oncogene Ras GTPase stimulates transcription of p21Waf1/Cip1 (p21), which is repressed by the RhoA GTPase. We previously showed that Ras also elevates p21 protein levels by reducing its proteasome-mediated degradation. Therefore, we investigated whether RhoA also influenced p21 protein degradation. Pulse-chase analysis of p21 protein stability revealed that inhibitors of Rho function, which disrupt filamentous actin (F-actin), drastically slowed p21 degradation. Direct F-actin disruption mimicked Rho inhibition to stabilize p21. We found that Rho inhibition, or F-actin disruption, activated the JNK stress-activated protein kinase, and that interfering with JNK signalling, but not p38, abrogated p21 stabilization by Rho inhibition or F-actin-disrupting drugs. In addition, Ras-transformation led to increased constitutive JNK activity that contributed to the elevated p21 protein levels. These data suggest that p21 stability is influenced by a mechanism that monitors F-actin downstream of Rho, and which acts through a pathway involving activation of JNK. These results may have significant implications for therapies that target Rho-signalling pathways to induce p21-mediated cell-cycle arrest.

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References

  • Adnane J, Bizouarn FA, Qian Y, Hamilton AD, Sebti SM . (1998). Mol Cell Biol 18: 6962–6970.

  • Aktories K, Mohr C, Koch G . (1992). Curr Top Microbiol Immunol 175: 115–131.

  • Assoian RK, Zhu X . (1997). Curr Opin Cell Biol 9: 93–98.

  • Beltman J, Erickson JR, Martin GA, Lyons JF, Cook SJ . (1999). J Biol Chem 274: 3772–3780.

  • Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC et al. (2001). Proc Natl Acad Sci USA 98: 13681–13686.

  • Bergo MO, Gavino BJ, Hong C, Beigneux AP, McMahon M, Casey PJ et al. (2004). J Clin Invest 113: 539–550.

  • Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM . (2004). Genes Dev 18: 862–876.

  • Bohmer RM, Scharf E, Assoian RK . (1996). Mol Biol Cell 7: 101–111.

  • Bottazzi ME, Zhu X, Bohmer RM, Assoian RK . (1999). J Cell Biol 146: 1255–1264.

  • Chardin P, Boquet P, Madaule P, Popoff MR, Rubin EJ, Gill DM . (1989). EMBO J 8: 1087–1092.

  • Coleman ML, Marshall CJ, Olson MF . (2003). EMBO J 22: 2036–2046.

  • Coleman ML, Marshall CJ, Olson MF . (2004). Nat Rev Mol Cell Biol 5: 355–366.

  • Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF . (2001). Nat Cell Biol 3: 339–345.

  • Danesh FR, Sadeghi MM, Amro N, Philips C, Zeng L, Lin S et al. (2002). Proc Natl Acad Sci USA 99: 8301–8305.

  • Denoyelle C, Albanese P, Uzan G, Hong L, Vannier JP, Soria J et al. (2003). Cell Signal 15: 327–338.

  • Denoyelle C, Vasse M, Korner M, Mishal Z, Ganne F, Vannier JP et al. (2001). Carcinogenesis 22: 1139–1148.

  • Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T et al. (1994). Cell 76: 1025–1037.

  • Escote X, Zapater M, Clotet J, Posas F . (2004). Nat Cell Biol 6: 997–1002.

  • Fang F, Orend G, Watanabe N, Hunter T, Ruoslahti E . (1996). Science 271: 499–502.

  • Fuchs SY, Fried VA, Ronai Z . (1998). Oncogene 17: 1483–1490.

  • Han S, Sidell N, Roman J . (2005). Cancer Lett 219: 71–81.

  • Harrison JC, Bardes ES, Ohya Y, Lew DJ . (2001). Nat Cell Biol 3: 417–420.

  • Hill CS, Wynne J, Treisman R . (1995). Cell 81: 1159–1170.

  • Huang S, Ingber DE . (2002). Exp Cell Res 275: 255–264.

  • Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S . (1999). Nat Med 5: 221–225.

  • Kim GY, Mercer SE, Ewton DZ, Yan Z, Jin K, Friedman E . (2002). J Biol Chem 277: 29792–29802.

  • Lee S, Helfman DM . (2004). J Biol Chem 279: 1885–1891.

  • Lew DJ . (2003). Curr Opin Cell Biol 15: 648–653.

  • Liberto M, Cobrinik D, Minden A . (2002). Oncogene 21: 1590–1599.

  • Lloyd AC, Obermuller F, Staddon S, Barth CF, McMahon M, Land H . (1997). Genes Dev 11: 663–677.

  • McCarthy SA, Samuels ML, Pritchard CA, Abraham JA, McMahon M . (1995). Genes Dev 9: 1953–1964.

  • Meier R, Rouse J, Cuenda A, Nebreda AR, Cohen P . (1996). Eur J Biochem 236: 796–805.

  • Muda M, Theodosiou A, Rodrigues N, Boschert U, Camps M, Gillieron C et al. (1996). J Biol Chem 271: 27205–27208.

  • Olson MF, Ashworth A, Hall A . (1995). Science 269: 1270–1272.

  • Olson MF, Paterson HF, Marshall CJ . (1998). Nature 394: 295–299.

  • Paterson HF, Self AJ, Garrett MD, Just I, Aktories K, Hall A . (1990). J Cell Biol 111: 1001–1007.

  • Pumiglia KM, Decker SJ . (1997). Proc Natl Acad Sci USA 94: 448–452.

  • Qiu RG, Chen J, McCormick F, Symons M . (1995). Proc Natl Acad Sci USA 92: 11781–11785.

  • Ren XD, Kiosses WB, Schwartz MA . (1999). EMBO J 18: 578–585.

  • Reshetnikova G, Barkan R, Popov B, Nikolsky N, Chang LS . (2000). Exp Cell Res 259: 35–53.

  • Ridley AJ, Hall A . (1992). Cell 70: 389–399.

  • Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A . (1992). Cell 70: 401–410.

  • Riento K, Ridley AJ . (2003). Nat Rev Mol Cell Biol 4: 446–456.

  • Sahai E, Marshall CJ . (2002). Nat Rev Cancer 2: 133–142.

  • Sahai E, Olson MF, Marshall CJ . (2001). EMBO J 20: 755–766.

  • Sampath P, Pollard TD . (1991). Biochemistry 30: 1973–1980.

  • Sanchez I, Hughes RT, Mayer BJ, Yee K, Woodgett JR, Avruch J et al. (1994). Nature 372: 794–798.

  • Spector I, Shochet NR, Kashman Y, Groweiss A . (1983). Science 219: 493–495.

  • Subbaramaiah K, Hart JC, Norton L, Dannenberg AJ . (2000). J Biol Chem 275: 14838–14845.

  • Tanaka H, Yamashita T, Asada M, Mizutani S, Yoshikawa H, Tohyama M . (2002). J Cell Biol 158: 321–329.

  • Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T et al. (1997). Nature 389: 990–994.

  • Walker K, Olson MF . (2005). Curr Opin Genet Dev 15: 62–68.

  • Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M . (1997). Mol Cell Biol 17: 5598–5611.

  • Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H et al. (2003). J Biol Chem 278: 52919–52923.

  • Yujiri T, Fanger GR, Garrington TP, Schlesinger TK, Gibson S, Johnson GL . (1999). J Biol Chem 274: 12605–12610.

  • Zhu X, Ohtsubo M, Bohmer RM, Roberts JM, Assoian RK . (1996). J Cell Biol 133: 391–403.

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Acknowledgements

We thank S. Sebti (University of South Florida, Tampa, Florida) for the gift of GGTI-298. This study was supported by Cancer Research UK and a National Cancer Institute grant R01 CA030721 to M. Olson.

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Correspondence to M F Olson.

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Coleman, M., Densham, R., Croft, D. et al. Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton. Oncogene 25, 2708–2716 (2006). https://doi.org/10.1038/sj.onc.1209322

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